The clinical data requirements to support a marketing authorisation application (MAA) for a new innovative medicine are extensive, and are frequently underestimated by companies with limited experience in bringing new medicinal products to the market. The CHMP frequently sees MAA dossiers (or proposals at the scientific advice stage) that fall well short of regulatory expectations and stand little or no chance of success. In such cases a product may fail entirely, even if it seems likely to be efficacious, acceptably safe and  of real clinical value. This is a bad outcome for all involved and for public health. Regulators can generally only draw conclusions based on robust data, not on assumptions or unjustified extrapolations.  It is essential  from the outset that the development of a new medicine is planned so that all data that will be expected during the MAA evaluation can be provided.  It is also important to know how best to adapt the plans to take account of events as they unfold e.g. a study that does not fully achieve its objectives. Common mistakes include the following. 

• Over-ambitious assumptions regarding anticipated study results
• Over-ambitious expectations for the recruitment, conduct and completion of studies 
• Neglecting the principle of the need to replicate scientific findings where there is a possibility of uncertainty 
• Methodological weaknesses in the design. conduct and analyses of studies, leading to concerns over the robustness and reliability of the data
• Failure to establish a suitable dose regimen prior to conducting pivotal studies
• Failure to adequately address any potential safety issues identified from early clinical data, animal data, or from the known pharmacology of the medicine. Where there is uncertainty on potentially important safety concerns, even if a signal seems quite likely to be a chance finding, further data to provide clarification are often expected before a marketing authorisation can be granted
• Neglecting the need to fully document key aspects of the clinical pharmacology

It is not uncommon for MAA dossiers to be incomplete at the time of submission. In some cases it may be acceptable to submit further, or more mature, data during the procedure or as a post approval commitment. Other possibilities may include conditional MA (CMA) or approval under exceptional circumstances (EC).  We have a clear understanding of the data that CHMP would require prior to full approval, what might be acceptable to be provided during the procedure or as a post approval commitment, and the situations where CMA or EC might be viable options. This allows us to provide the best possible gap analysis of a proposed development programme. 

Whatever strategy is appropriate for the specific situation, we can help to ensure that the clinical development plan is optimal, as far as possible, to provide the data expected by CHMP for a potential positive opinion. 

CHMP scientific advice is generally of a high quality and for the most part we would advise companies to seek it and to follow it, unless there are good reasons not to. A company may find itself in a difficult position however, if the CHMP advice diverges substantially from the company's plans after due consideration of the CHMP position. This may occur for example if the advice does not sit well with the expectations of other regulators such as the FDA, or if the CHMP proposals are problematic in terms of resource limitations, timelines or other practical considerations.  If an alternative approach is likely to be sufficient to obtain the necessary data to meet the requirements for a MA application, and to confirm a positive benefit / risk balance, there is no reason in principle why it could not be acceptable. There is no obligation to follow CHMP advice, and in this regard it differs somewhat from some FDA requirements. However it would be unwise to deviate substantially from the CHMP advice without a clear understanding of the possible consequences. There are numerous examples where the failure of a new medicine to achieve a European MA can be attributed to the company choosing not to take the CHMP's advice, with the result that CHMP was not persuaded that efficacy had been reliably demonstrated.  Issues that have caused such problems include choice of comparators in clinical trials, including the use of historical data, the choice of efficacy endpoints and the nature of the trial populations.  It is not uncommon for trial designs that meet FDA requirements to be unacceptable to EU regulators. We can help to clarify where it would be very unwise not to comply with the CHMP advice, and where a different approach might reasonably be taken.

Clinical trials generate enormous amounts of data and it is extremely important to present the most relevant data effectively in the dossier for a Marketing Authorisation Application (MAA). We can review proposals for the structure and content of the clinical parts of the dossier (in particular modules 2.5, 2.7 and 5) and give advice on how best to present the data to facilitate assessment. It is essential that assessors are able to find the information that they need quickly and easily. If they cannot, the inevitable result will be a long list of questions and potentially a more negative preliminary view on the approvability of the product than might otherwise be the case. It is hard to over-state the importance of presenting the data effectively in the dossier and we can help to ensure that this is achieved, to minimise difficulties later, during the MAA procedure. 

The approach taken to addressing any Major Objections to the CHMP's list of questions can be critical to the success or failure of an application. It is not uncommon for a potentially approvable application to require an oral explanation, often because of unsatisfactory written responses to key questions. We can help to ensure as far as possible that written responses provide the data, discussions and justifications necessary to reassure the assessors and CHMP.  

If an application requires an oral explanation or a re-examination procedure following a negative opinion, it becomes critically important to fully understand the nature of CHMP's concerns and how best to address them. The rapporteurs and EMA will give some general advice, but not the detailed support and expert advice that Centralised Pharma can provide in addressing the remaining concerns. Greg's experience from hundreds of CHMP oral explanations brings a deep understanding of how the current CHMP thinks and how best to persuade them. It could make all the difference where the outcome is in the balance.

An independent, expert evaluation of clinical trial data can be of great value for various reasons other than the need to meet regulatory requirements. For example, at various stages in early drug development key decisions need to be taken regarding future investment in a new medicine. Typically these decisions are taken based on very limited data, around which there are considerable uncertainties. The parties making investment decisions are typically dependent on others for the relevant scientific evaluations. Researchers and clinical key opinion leaders may have limited expertise in evaluating the results of clinical trial data, especially in determining the robustness and reliability of the results, and hence the likelihood that encouraging looking results might be due to factors other than a true and clinically relevant treatment effect. Furthermore, in our experience small companies may be unduly optimistic about the prospects for a new product that they have spent much time, energy and money developing. Unfortunately the belief is not always supported by the scientific facts. Centralised Pharma can provide a dispassionate expert evaluation of the available early phase clinical data and provide a report discussing the conclusions that can reasonably be drawn from these data.